NMR spectroscopy as a tool to investigate the structural basis of anticancer drugs.
NMR spectroscopy has been shown to be useful in determining the structures of nucleic acid fragments in solution. Over the last several years NMR spectroscopy, in conjunction with restrained molecular dynamics, has been employed to understand the 3D structures of a number of anticancer drugs and to rationalize their DNA binding behavior. In this review we address the methodologies used most frequently to determine nucleic acid structures in solution. In subsequent sections, we examine how these methods have been applied to rationalize the activities of a number of anticancer agents that target duplex DNA such as cisplatin, bleomycin and calicheamicin. Non-duplex DNA and RNA also represent interesting nucleic acid targets for anticancer drug design and applications of solution NMR spectroscopy to understanding the structures of these types of molecules (e.g. Okazaki fragments, DNA tetraplexes) are also reviewed. In the final sections, advances in NMR methodologies (e.g. linear prediction, superconducting probes) that are likely to impact the research conducted in this area are reviewed. The success of NMR spectroscopy in understanding the structural basis for clinically useful anticancer drugs bodes well for future applications of this methodology not only in rationalization of existing biological activity, but in the design of novel agents that will be useful in treating neoplastic disease.
Gmeiner
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UNMC/Eppley Cancer Center, @ 600 S. 42nd St., Omaha, NE 68198-6805, USA.
D000970:Antineoplastic Agents / Q000737:chemistry*; D004247:DNA / Q000737:chemistry; D004273:DNA, Neoplasm / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D007364:Intercalating Agents; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D012313:RNA / Q000737:chemistry
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D007364:Intercalating Agents; D012313:RNA; D004247:DNA